Asymmetrical diamides of tetraiodoterephthalic acid

ABSTRACT

Asymmetrical diamides of tetraiodoterephthalic acid having the general formula In these formulas, X is lower alkylene or phenyl-lower-alkylene, R is hydrogen, lower alkyl or phenyl-lower alkyl. X and R may also jointly be alkylene forming a heterocyclic ring with the associated nitrogen atom. R1 is hydrogen or lower alkyl, R2 is lower alkyl, carboxy-lower-alkyl, or lower-carbalkoxy-lower-alkyl or R1 and R2 jointly are lower-alkyleneoxy-lower-alkylene, carboxy-lower-alkylene or lower-carbalkoxy-lower-alkylene. R3 is hydrogen, lower alkyl, non-toxic amine or non-toxic alkali metal or alkaline earth metal, the amine or metal being selected to make the diamide water soluble.

United States Patent Suter et al.

[ 51 Sept. 12, 1972 [541 ASYMMETRICAL DIAMIDES OF TETRAIODOTEREPHTHALICACID Inventors: Hans Suter, Dorflingen; Hans Zutter; Josef Brunner, bothof Schaffhausen, all of Switzerland Eprova Aktiengesellschaft,Schaffhausen, Switzerland Filed: Nov. 10, 1969 Appl. No.: 875,594

[73] Assignee:

[30] Foreign Application Priority Data Nov. 20, 1968 Switzerland..l7276/68 [52] US. Cl ..260/326.3, 260/247.2 A, 260/518 A, 260/471 A,424/5 Int. Cl. ..C07d27l04 Field of Search ..260/326.3, 518 A, 471 A,260/247.2 A

[56] References Cited UNITED STATES PATENTS 3,042,715 7/1962 Obendorf etal 260/518 Primary Examiner-Alex Mazel Assistant Examiner-Joseph A.Narcavage Attorney-Kelman and Berman [5 7 ABSTRACT Asymmetrical diamidesof tetraiodoterephthalic acid having the general formula are relativelynon-toxic and are preferentially accumulated in the gall bladder ofwarm-blooded animals when ingested, injected or applied rectally.Because of their high iodine content, they are effective contrastagents, particularly in cholecystography. They are prepared from mixedanhydrides of tetraiodoterephthalic acid by sequential reaction withamines of the formulas H-N-R,

I l; (II) and HNX-C 0 0 R3 12 Claims, No Drawings ASYMMETRICAL DIAMIDESOF TETRAIODOTEREPHTHALIC ACID This invention relates to X-ray contrastmedia, and particularly to iodine bearing organic compounds suitable foruse as contrast agents in cholecystography, and to the preparing andcompounding of such compounds.

Several iodine-bearing organic compounds have been in clinical useheretofore as contrast agents in cholecystography. The known contrastagents are relatively toxic as compared to similar compounds presentlyused for visualizing the blood vessels and the urinary tract, and theydo not accumulate in the gall bladder in sufficient amounts to giveadequate opacity when used in safe amounts.

It has now been found that certain asymmetrical diamides oftetraiodoterephthalic acid combine the'three principal propertiesnecessary for good cholecystographic contrast' agents in a morefavorable manner than was'available until now. Because the compoundscontain four iodineatoms in the molecule, their iodine content'and theresulting opacity to X-rays are high.

The compounds tend to accumulate in the gall bladder when applied bymouth, rectally or parenterally. Their toxicity in effective doses istoo low to produce significant sideeffects.

The compounds of the invention have the formula pound water soluble. Theterm lower will be understood to limit the alkyl or alkylene radicalreferredto to not more than five carbon atoms.

Best results are obtained in cholecystography with the compounds of theinvention which are either carboxylic acids or metal or amine salts ofsuch carboxylic acids. While there are some indications of limitedutility as contrast agents for the esters of carboxylic acidsencompassed by the above formula, the esters are mainly useful asintermediate in the preparation of the free acids and of their salts.

Representative compounds of the invention (Compounds A to' R) are listedbelow together with tetraiodophthalic acid (Compound S) and similarcompounds (Compounds T to V) which have been disclosed, respectively, inthe German Patent No. 1,112,251, US. Pat. No. 2,247,880, and GermanPatent 1,066,707. For comparison purposes, reference will be hadhereinbelow to derivatives of triiodobenzene which are in currentclinical use or were proposed heretofore as contrast agents incholecyctography: adipiodone or iodipamide (Compound W), ioglycamic acid(Compound Y) and iopanoic acid (Compound Z).

C. 4-(4-N-aCarboxy--y-methylbutylcarbamyl-2,3,5 ,6-

tetraiodobenzoyl)morpholine D.4-(4-N-Methyl-N-carboxymethylcarbamyl-2,3,5,6-

tetraiodobenzyl)-morpholine E. tetraiodobenzoyl)-morpholine F.4-[4-(2'-Carboxy-pyrrolidino)-carbonyl-2,3,5,6-tetraiodobenzoyl]-morpholine G. B-(4-N-Methylcarbamyl-2,3,5,6-tetraiodobenzyl)amino-a-phenyl-propionic acid H.1-(4-N-Methylcarbamyl-2,3,5,6-tetraiodobenzoyl)-pyrrolidine-2-carboxylic acid I. N-( 4-N '-Carboxymethylcarbamyl-2,3 ,5,6- tetraiodobenzoyl)-N-methyl-amino-acetic acid K.B-(4-N-Carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-amino-a-ethyl-propionic acid L.B-(4-N-Carboxymethylcarbamyl-2,3,5 ,6-tetraiodobenzoyl)-amino-a-phenyl-propionic acid M.N-(4-N'-Carboxymethylcarbamyl-2,3 ,5 ,6-tetraiodobenzoyl)-N-ethyl-amino-acetic acid N.N-(4-N'-Carboxymethylcarbamyl-2,3,5,6- tetraiodobenzoyl)-N-benzoyl-amino-acetic acid 0. l-(4-N-Carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl )-pyrrolidine-2-carboxylic acid P.B-(4-N-Methyl-N-carboxymethylcarbamyl-2,3,5,6- tetraiodobenzoyl)-amino-a-ethylpropionic acid Q. ,B-[4-(2Carboxypyrrolidine)-carbonyl-2,3,5,6-tetraiodobenzoyl]-amino-a-ethylpropionic acid R. 1(4-N-Methyl-N-carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-pyrrolidine-Z-carboxylic acid S. Tetraiodophthalicacid T. Morpholide of tetraiodophthalic acid U. Tetraiodoterephthalicacid V. N,N-Tetraiodoterephthalic acid diglycide.

Table 1 lists toxicity values and data on bilitropism for Compounds A toZ. The toxicity values were determined on mice by standardizedconventional procedures and are expressed as DL, in mg/kg. The

compounds were applied orally and/or by intravenous injection of aqueoussolutions of their sodium and/or -N-methylglucamine salts-over a periodof 30 seconds.

Not all tests were performed on all compounds.

To evaluate bilitropism, the tendency of a compound to be excretedpreferentially by the liver with the bile, rabbits were injectedintravenously with aqueous salt solutions of the free acids listedabove, and the percentages of the active material excreted through thegall bladder and with the urine were determined after three hours. Thelisted ration of excretion with the bileto excretion with the urine is ameasure of bilitropism.

4-(4-N-a-Carboxybutylcarbamyl-2,3 ,5 ,6-

, 4-(4-'y-Carboxypiperidinocarbonyl-2,3,5,6-

L 2,800 59 15.5 3.8 M 7,300 30 28 1.07 N 3,780 63 34 L85 6,400 41 420.97 P 4,000+ 33.5 32 1.01 Q 4,000+ 37.5 34 1.1 R 4,000+ 35.5 28 1.27 s100 T 670 1 1 41 0.27 U 5.300 2 80 0.025 v 10,000+ 6,000 24 55 0.44 w2,400 37 38 0.98 Y 4,200 30 41 0.73 2 1,540 285 28 13 2.15

Table ll lists the results obtained in the cholecystography of dogs l)and/or cats (2) at various times after application of the testedcompounds by intravenous injection at a dosage of 100 mg compound perkilogram body weight (a) or of 165.6 mg iodine equivalent per kg (b).The density of the gall bladder shadow in each X-ray image and thecontrast quality of the image were evaluated by the method of J .O.l-loppe [.I. Am. Pharm.

Assn. Sci. Ed. 48, 368-379, (1959)]. On the Hoppe scale, 0 indicates anegative result, 1 weak, 2 adequate, 3 good, and 4 excellent.

TABLE ll Hoppe Index, after Animal/ Compound Dosage 1 hr. 2 hrs. 4 hrs.6 hrs. 8 hrs. 24 hrs.

wherein X, R, R R have the same meaning as in Formula (1) above. Thereaction product may be saponified if R is alkyl, and the free acid orsalt so obtained may be converted to another salt or to the free acid ifso desired. The asymmetrical diamide ultimately obtained is combinedwith an inert excipient in a conventional manner to produce aninjectable, ingestible or rectally applicable composition.

Generally, the reactive diacyl derivative of tetraiodoterephthalic acidis reacted first with an amine of one of the two formulas (ll) and (Ill)until a monoamide of tetraiodoterephthalic acid having one reactive acylderivative group is formed, and the monoamide is thereafter reacted withthe amine of the other formula. The sequence in which the amines arereacted with the tetraiodoterephthalic acid derivative is not important,and similar yields are usually obtained by either sequence of reactions.

The preferred reactive diacyl derivatives of tetraiodoterephthalic acidare the mixed anhydrides with inorganic and organic acids such as thehydrogen halides and azides, tetraiodophthaloyl dichloride, (dibromide,diiodine or diazide), oxygen and phosphorus bearing acids(tetraiodoterephthaloyl diphosphite), carboxylic acids(1,4-bisacyl-oxycarbonyl-2,3,5,6-tetraiodobenzene), or the semi-estersof carbonic acid (1 ,4-bisalkoxycarbonyloxycarbonyl-2,3,5 ,6-tetraiodobenzene).

The diamides of the invention in the free acid form, in which R ishydrogen, are generally insoluble or poorly soluble in water, butreadily dissolve in alkaline aqueous media. They are therefore usedconveniently in dosage units for oral application. The salts withnontoxic alkali metals and alkaline earth metals and with the non-toxicamines commonly employed in pharmaceutical chemistry for solubilizingtherapeutically or otherwise effective anionic radicals are soluble inwater or almost miscible with water. Such soluble non-toxic saltsinclude those of sodium, lithium, calcium, magnesium, and of thenonl-toxic alkanolamines such as diethanolamine or N-methylglucamine.The morpholine salts are also generally water soluble and many otheramine salts are obviously available.

The toxicity, bilitropism, and iodine content of each salt arepractically unaffected by the associated cationic component, and notsignificantly different from the corresponding properties of the freeacids.

The following Examples l- 16 are further illustrative of the compoundsof the invention and of the methods of preparing and using the same.

EXAMPLE 1 4-(4-N-a-Carboxybutylcarbamyl-2,3,5,6-tetraiodobenzoyl)-morpholine (Compound B) and Homologs 3.48 g Morpholinewere added drop by drop to a solution of 14.12 g tetraiodoterephthaloyldichloride (0.020 mole) in l54 ml dimethylformamide at 20 C. Thereaction was permitted to proceed for 30 minutes, and ice water was thenadded until no further precipitation occurred. The resulting suspensionwas acidified with 2 N HCl and filtered with suction. The solidrecovered and dried (14.56 g) consisted of 4-(4-chloroformyl-2,3,5,6-tetraiodobenzoyl)-morpholine, a littletetraiodotetraphthaloyl dimorpholide, and unreactedtetraiodoterephthaloyl dichloride. It was dissolved in 250 ml chloroformand extracted with a total of 30 ml concentrated sulfuric acid. 6.4 g.Pure tetraiodoterephthaloyl dichloride were recovered from thechloroform phase after washing with water and evaporation of thesolvent.

The sulfuric acid extract was poured over ice, and a finely crystallineprecipitate was formed. It was filtered off with suction and repeatedlywashed with water. It consisted of tetraiodotetraphthaloylmonomorpholide and a small amount of the dimorpholide. It was heated toboiling with sufficient 1 N NaOH (53 54 ml) to make the pH 8.5 9. Theundissolved dimorpholide was removed by filtration of the hot mixture,and the filtrate was mixed with an excess of hydrochloric acid toprecipitate the monomorpholide. It was recovered in an amount of 6.1 g,had a melting point of 193 198 C, and was identified by elementaryanalysis:

It can be purified, if so desired, by crystallizing the sparinglysoluble sodium salt from water.

5 g Tetraiodoterephthaloyl monomorpholide were mixed with ml phosphorusoxychloride and 6 g phosphorus .pentachloride. The chlorination mixturewas held at 100 to 105 C for two hours. The almost clear solution wasthen evaporated in a vacuum. and the residue was carefully transferredto ice. The crude acyl chloride so obtained was purified by brieflysuspending it in warm, dilute sodium hydroxide solution in whichunreacted tetraiodoterephthaloyl monomorpholide was dissolved. Thesuspension, while still hot, was filtered with suction, and therecovered solid intermediate was washed with much water. When dried, itweighed 4.4 g (88 percent yield) and consisted of chromatographicallypure 4-4-'chloroformyl-2,3,5,6- tetraiodobenzoyl)-morpho1ine of MP. 260265 C. the compound was identified by elementary analysis:

Calc. for C ll ,,Cll,N0 Found 5 equ. total halogen 4.9

A mixture of 12.5 g of the last-mentioned intermediate in 190 mldimethylformamide with 5.41 g DL- norvaline in 41.5 ml l-N NaOH wasstirred for four hours at 100 C. 700 Ml dilute hydrochloric acidcontaining 45 ml l-N HCl were added, and the resulting precipitate wasfiltered with suction at 0 C and well washed with water. It wasdissolved in aqueous sodium hydroxide solution and reprecipitated fromthe filtered solution with an excess of hydrochloric acid, and the l 1.6g of impure Compound B were further purified by recrystallization from55 ml ethanol. The yield was 9.5 g (69 percent) of pure Compound Bmelting at 278 280 C, and having an R, value of 0.90 in a thin layerchromatogram on silica gel (acetone/chloroform/gla cial acetic acid5:4:1). All R, values reported hereinbelow were obtained on the samesubstrate with the same solvent system, unless stated otherwise.

The compound is insoluble in water, only sparingly soluble in mostorganic solvents, but readily soluble in dimethylsulfoxide. It wasidentified by elementary analysis:

Calculated for C H 1,N,0, 24.4% C; 60.6% I Found 24.4 60.8

At 20 C, the solubility of the sodium salt is 33 g/dl, that of theN-methylglucamine salt 30 g/dl.

Compound C was obtained when L-leucine was substituted in the aboveprocedure for DL-norvaline, and

Compound M.P. "C R,.

C 282 283.5 0.91 A 268 271 0.94 AA 292 295 0.81 BB 275 281 0.91 CC 268271 0.94

The sodium and N-methylglucamine salts of the five acids tabulated aboveare soluble in water at 20 C, while the free acids are insoluble inwater. Compound C is soluble in lower alkanols, acetone and glacialacetic acid, but only trace amounts dissolve in ethers and hydrocarbons.Compound A is somewhat soluble in hot methanol, but only slightlysoluble in other common organic solvents. Compound CC is insoluble inmost organic solvents.

EXAMPLE 2 4-(4N-Methyl-N-carboxymethylcarbamy1-2,3,5,6-tetraiodobenzoyl)-morpholine (Compound D) 21.3 g Sarcosine ethyl esterin 300 ml chloroform were refluxed for five hours with 34.0 g4-(4-chloroformyl-.2,3,5 ,6-tetraiodobenzoyl)-morpholine. The chloroformsolution was extracted with dilute hydrochloric acid and with water andwas thereafter evaporated to dryness. The residue (30.5 g) consisted ofthe ethyl ester of Compound D which was identified by elementaryanalysis.

Calculated for Cl1H2|t l 2 5 Found I The crude ester was hydrolyzed in aboiling solution prepared from 63 ml 3-N methanolic NaOH solution mlmethanol and 54 ml aqueous, l-N sodium hydroxide solution. The sodiumsalt of Compound D precipitated from the hydrolyzation mixture, wasfiltered off with suction, washed with a little methanol and dissolvedin pure water. The chromatographically pure Compound D was precipitatedfrom the clear solution with an excess of 2-N hydrochloric acid in anamount of 17.4 g (48 percent yield) and had a melting point of 287 289C. lts thin layer chromatogram gave an R; value of 0.4.

The free acid is insoluble in water, somewhat soluble in hot methanolbut very sparingly soluble in other common organic solvents.

EXAMPLE 3 4(4--y-Carboxypiperidinocarbonyl-2,3,5,6-tetraiodobenzoyl)-morpholine (Compound E) 18.95 g (0.025 Mole)4-(4-chloroformyl-2,3,5,6- tetraiodobenzoyl)-morpho1ine and 17.3 g ethylpiperidine-4-carboxylate (0.1 1 mole) were dissolved in 260 ml dioxan,and the solution was heated at 70 C for two hours. 275 Ml water wereadded dropwise, and the mixture was cooled to C. 29.65 g Pure ethylester of Compound E precipitated. It was saponified at boilingtemperature in 250 ml dioxan with 100 ml 2.85 N methanolic sodiumhydroxide solution and 40 ml water. The solution of the sodium salt wasmixed with 150 ml water, and 400 ml 2 N hydrochloric acid were added toprecipitate the free acid which was filtered with suction at 0 C andwashed with water.

24.07 g Compound E were recovered (55 percent yield). The Compound has amelting point of 304 306 C and was identified by its equivalent weightfound to be 850 (calculated 848). Its R, value was 0.64. The compoundisinsoluble in water and in most organic solvents. 1

EXAMPLE 4 4-[4-(2'-Carboxypyrrolidino)-carbonyl-2,3,5,6-tetraiodobenzoyl]-morpholine (Compound F) A mixture of 37.85 g (0.050mole) 4-(4-chloroformyl-2,3,5,6-tetraiodobenzoyl)-morpholine, 12.9 g(0.090 mole) L-proline ethyl ester, 5.05 triethylamine, and 250 mldichloroethane was refluxed with, agitation for 12 hours. The reactionmixture was cooled to ambient temperature, extracted with three batchesof 200 ml 0.2 N hydrochloric acid and repeatedly extracted with water.The clear solution was dried over desiccated sodium sulfate andevaporated to dryness. The residue having a light buff color wasrecrystallized from 100 ml ethanol. 32.85 g4-[4-(2'-carbethoxypyrrolidine)-carbonyl-2,3,5,6-tetraidobenzoyl]-morpholine of MP. 237 232 C (76 percent yield) were recovered, andconsisted of a mixture of two isomers.

28.0 Grams of the ethyl ester were saponified while suspended in 150 mlboiling ethanol to which 50 ml 1- N NaOH solution were gradually added.The resulting clear solution was diluted with 100 ml water and wasfurther refluxed gently for 30 minutes. The almost colorless solutionwas evaporated to dryness, the residue was dissolved in water, and theaqueous solution was purified with active carbon, and acidified with anexcess of 2 N HCl. The precipitated Compound F was filtered off withsuction and washed with water until free from chloride.

22.1 g Compound F were recovered (81 percent yield). The Compoundsintered at above 230 C and decomposed at 275 C. The two isomers hadrespective R, values of 0.67 and 0.76. An equivalent weight of 836 wasfound (calculated for C l-l hN O z 835.2).

EXAMPLE 4-N-Methylcarbamyl-2 ,3 ,5 ,6-tetraiodobenzoylaminoacetic acid(Compound DD) A boiling solution of 19.8 tetraiodoterephthaloyldichloride in 315 ml chloroform was mixed with 5.2 g 33 percentmethylamine in chloroform. The mixture was stirred at the boilingtemperature for 40 minutes, and the precipitate formed was filtered offwith suction and washed with chloroform. It was extracted repeatedlywith a total amount of 250 ml boiling dioxan,

and the dioxan solution was evaporated until the viscous residue ofcrude 4-N-methyl-carbamyl-2,3.5 ,6- tetraiodobenzoyl chloride wasobtained. When treated with acetone, the chloride crystallized. It wasrecrystallized from 140 ml dimethylformamide and 400 ml acetone. Thepure compound weighed 12.6 g (64 percent yield) and melted at 288 291 C.

14.0 g Chloride prepared as described in the preceding paragraph and4.53 g glycine were suspended in 200ml dimethylformamide and. 60 ml 1.0N sodium hydroxide, and the mixture was stirred for six hours at 105 108C, whereby a clear solution was formed. 80

Ml hydrochloric acid (1:1) were added drop by drop,

Calculated for C,,1-1,,1;N,0, Found' EXAMPLE 6N-(4-N'-Methylcarbamyl-2,3,5,6-tetraiodobenzoyl)- N-methylaminoaceticacid (Compound EE) 21.04 g (0.03 Mole) 4-N-methylcarbamyl-2,3,5,6-tetraiodobenzoyl chloride were dissolved in 500 ml dioxan at 20 C. 14.1g Sarcosine ethyl ester were added, and the mixture was stirred at 20 25C for about 42 hours, and thereafter for 3 hours at C. It was thencooled to ambient temperature, and the unreacted sarcosine ester wasprecipitated as the hydrochloride by means of an excess of l-lCl inether and removed by filtering. The filtrate was evaporated until aviscous, sirupy residue was obtained. When diethyl ether was added, theresidue crystallized. It was filtered with suction, and 23.8 g of thecrude ethyl ester of Compound EE were obtained. After recrystallizationfrom 300 ml methylethylketone, 13.8 g of the pure ester were obtained.It sintered at 126 137 C, and melted at 233 235 C.

It was saponified in hot methanolic sodium hydroxide solution to whichwater was added gradually at a rate to keep the solution clear. After 15minutes of refluxing, the saponification mixture was evaporated todryness, and the residue was dissolved in water from which the free acid(Compound EE) was precipitated by an excess of hydrochloric acid. Itweighed 12.8 g (56 percent yield), melted at 288 291 C, had an R, valueof 0.75, and was identified by elementary analysis.

Calculated for C 1-1 ,,1 N,0., Found EXAMPLE 7B-(4-N-Methylcarbamyl-2,3,5,6-tetraiodobenzoyl)- amino-a-phenylpropionicacid (Compound G) A solution of 35.0 g 4-N-methylcarbamyl-2,3,5,6-tetraiodobenzoyl chloride (0.05 mole) in 250 ml dimethylformamide wasmixed with 14.5 g ethyl aphenyl-B-aminopropionate and 7.6 gtriethylamine. The mixture was kept for 90 minutes at 90 95 C, whereupon600 ml water and 100 ml 2 N hydrochloric acid were added. Abrownish-buff precipitate formed and was filtered off with suction at C.It was crystallized from 150 ml hot dimethylformamide by adding 250 mlacetone in an amount of 30.6 g (71.5 percent yield) astetraiodobenzoyl)-amino-a-phenylpropionate of MP. 342 348 C. v

27.0 Grams of the ethyl ester of Compound G were suspended in 675 mlethanol, the suspension was heated to refluxing temperature, and 450 ml1 N sodium hydroxide solution were 'slowly added. A solution was formedand was refluxed for an additional 2.5 hours. .Ultimately, .50 ml waterwere added, and the saponific'ation mixture was cooled to roomtemperature, whereby 15.1 g pure sodium salt of Compound G wereprecipitated in crystalline form. The crystals were dissolved in water,and the free Compound G was precipitated by an excess of hydrochloricacid 1:1. It was filtered off with suction, washed with much water anddried.

Compound G was obtained in an amount of about 13 g (35.5 percent'yield),melted at 301 303 C, and gave an R, value of 0.94. It was identified byelementary analysis. I

Calculated for C H LN, 61.2% 1

1-( 4.-N-Methylcarbamyl-2, 3 ,5 ,6-tetraiodobenzoylpyrrolidine-Z-carboxylic Acid (Compound H) A suspension of 28.0 g4-N-methylcarbamyl-2,3,5,6- tetraiodobenzoyl chloride and 1 1.51 gL-proline in 450 ml dimethylformamide and 100 ml 1.0 N sodium hydroxidesolution was stirred for 3.5 hours at 100 105 C. A clear, yellowsolution was obtained. When the reaction was completed, 120 m1 1 Nhydrochloric acid in 1,000 ml water were added, and the mixture wascooled until crude Compound H was crystallized. It was filtered off withsuction and repeatedly washed with water (21.2 g).

It was purified by treatment with 150 ml hot ethanol which appeared tocause a change in the crystal structure and in the geometricalconfiguration of the crystals. When filtered from the mother liquor andwashed with ethanol, 17.2 g of the pure Compound H were obtained (55percent yield), The compound melts at 220 221 C and gave an R; value of0.825. It was identified by elementary analysis:

Calculated for C,,H,,1 N,O

Found The acid is insoluble in water and soluble in boilingethyl-B-(4-N-methylcarbamyl-2,3,5,6,-

35 crude di-ester of Compound 1 was filtered off, dried,

bus solutions at room temperature, the N-methyl-glucamine salt 50percent solutions.

EXAMPLE 9 5 N-(4-N-Carboxymethylcarbamyl-2,3,5,6-

tetraiodobenzoyl)-N-methylamino acetic Acid (Compoundl) 18.0 g (0.0255Mole) tetraiodoterephthaloyl dichloride were dissolved in 80 ml drytetrahydrofuran,

*and 5.6g ethyl aminoacetate were added. The reaction mixture wasstirred 48 hours at ambient temperature, the resulting suspension wasfiltered, and the precipitate was washed twice on the filter with 20 mltetrahydrofuran. The filtrate and washings were evaporated to a volumeof 55 ml, and 40 ml petroleum ether (B.P. 60 90 C) were added to theboiling concentrate. A voluminous white precipitate was formed. It wasfiltered off at 20 C with suction and washed with a 1:1 mixture oftetrahydrofuran and petroleum ether.

Almost pure 4-N-carbethoxymethyl-carbamyl- 2,3,5 ,6-tetraiodobenzoylchloride of M.P. 231 -233 C was obtained in a'yield of 13, g (66percent). When recrystallized from chlorobenzene, it melted at 234 236C. A thin layer chromatogram on silica gel gave an R, value of 0.8 withhexane/chloroform/glacial acetic acid 5:421.

36.9 g (0.045 Mole)4-N-carbethoxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl chloride wereheated in 360 ml dimethylformamide to C and 16.0 g sarcosine ethyl esterwere added. The mixture was kept at 100 C for two hours, and theresulting clear solution was poured over a large amount of icecontaining an excess of hydrochloric acid. The precipitated dissolved in100 ml hot dimethylformamide, and crystallized in purified form byadding 200 ml acetone. It was filtered off at 0 C and washed repeatedlywith acetone. The pure ester was obtained in an amount of 29.5 g andmelted at 22 229 C.

The ester was suspended in 215 ml ethanol, and 104 ml 1.0 N sodiumhydroxide solution were added to the suspension at refluxingtemperature, whereby a clear solution was obtained. After about an hour,the solution was evaporated to dryness,-the residue was dissolved in 200ml water, and free Compound 1 was precipitated from the solution of thesodium salt by adding ml 1 N hydrochloric acid. It was recovered in anamount of 22.3 g (62 percent yield), melted at 199 201 C and gave an R;value of 0.488. It was identified by its equivalent weight and byelementary analysis:

Calculated for q. .,i-1,|.o., Found eq. wt. 399; 19.6% C; 63.6% I

EXAMPLE 10 N-( 4-N'-Carboxymethylcarbamyl-2,3 ,5 ,6-tetraiodobenzoyl)-N-ethylamino-acetic Acid (Compound M) and Homologs(Compound K) When sarcosine ethyl ester was replaced in the generalprocedure of Example 9 by the corresponding ethylaminoacetic acid ester,Compound M was obtained.

38.7 g 4-N-Carbethoxymethylcarbamyl-2,3,5,6- tetraiodobenzoyl chloride,13.1 g ethyl N- ethylaminoacetate, and 5.0 g triethylamine were stirredin 260 ml dimethylformamide at 100 C for four hours. The reactionmixture was poured into 1,500 ml water containing 250 ml 2 Nhydrochloric acid. The precipitated, finely crystalline diester wasfiltered off with suction, washed with water and recrystallized fromethanol. 19.2 g N-(4-N'-Carbethoxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-N-ethylaminoacetic acid ethyl ester (44.3percent yield) were obtained and melted at 186- 187.5 C.

15.0 g (0.017 Mole) of the diester were hydrolyzed in 150 ml ethanolwith 52 ml 1.0 N aqueous sodium hydroxide solution and two additions of50 ml water. Refluxing was continued for 30 minutes after the lastwateraddition, and the solution was evaporated to dryness. The residuewas dissolved in 200 ml water, and 6 ml concentrated hydrochloric acidwere added to the solution of the sodium salt to precipitate crudeCompound M which was filtered off and washed with water until free fromchloride. 1t weighed 13.0 g (94.2 percent yield), had a melting point of245 253 C, and

Calculated for C H LN O Found The free acid is insoluble in water,soluble in boiling lower alkanols, acetone, warm ethyl acetate andglacial acetic acid. The sodium and N-methylglukamine salts freelydissolve in water 20 g/dl).

a-Ethyl-Baminopropionic acid ethyl esterwhen substituted for theN-ethylaminoacetic acid ester gave [3-(4-N-carbethoxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-amino-a-ethylpropionic acid ethyl ester of M.P. 300302 C, in a yield of 86 percent. The diester was saponified to thesodium salt as described above, and the free acid,B-(4-N-carboxymethylcarbamyl-2,3,5,-tetraiodobenzoyl)-amino-aethylpropionicacid (Compound K) of MP. 293 295 C (Decomp.) and R, 0.64 was obtainedand identified by elementary analysis. It is insoluble in water, andinsoluble or only sparingly soluble in the usual organic solvents.Aqueous solutions stronger than 25 percent are readily prepared at roomtemperature from the sodium and N-methylglucamine salts.

EXAMPLE 1 l l-(4-N-Carboxymethylcarbamyl-2,3 ,5 ,6-tetraiodobenzoyl)-pyrrolidine-2-carboxylic acid (Compound O) andanalogous compounds (Compound N) The proline ethyl ester used in aprocedure closely similar to those of Examples 9 and 10 gave Compound 0.

A solution of 26.5 g (0.0343 mole)4-N-carbethoxymethylcarbamy1-2,3,5,6-tetraiodobenzoyl chloride[4-(4-chloroformyl-2,3,5,6- tetraiodobenzoylaminoacetic acid ethyl ester9.84 L- proline ethyl ester, and 2.50 g triethylamine in 220 ml1,2-dichloroethane was held at 78 80 C for 15 hours. The reactionmixture was extracted twice with 200 ml 0.2 N hydrochloric acid and fivetimes with ml water and evaporated to dryness. The residue wascrystallized twice from its hot saturated solutions in ethanol, and 18.7g chromatographically pure l-(4-N-carbethoxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-pyrrolidine-2-carboxylic acid ethyl ester (62.0 percent yield) wereobtained. The compound sintered to a transparent mass at 138 C.

5.90 g Diester in 30 ml ethanol were mixed hot with 30 ml 1.0 N sodiumhydroxide solution within five minutes. The solution so obtained wasdiluted with 30 ml water and refluxed for 1.5 hours. It. was thenevaporated until very viscous, dissolved in water, clarified with activecarbon, and acidified with an excess of hydrochloric acid. Theprecipitated Compound 0 was filtered off with suction and repeatedlywashed with water. The yield was 4.90 g (90.5 percent). The compoundmelted at above 230 C (Decomp.) and gave an R; value of 0.44. It wasidentified by its equivalent weight of 418 (calculated 421 for .C H ,1,NzO J-hO). The sodium and N-methylglucamine salts easily dissolve inwater at room temperature.

In an analogous manner, the crude diethyl ester of N-(4-N'-carboxymethylcarbamyl-Z,3,5,6- Itetraiodobenzoyl)-N-benzylaminoacetic acid (Compound N) was obtainedfrom N-benzylaminoacetic acid ethyl ester in a yield of 88 percent andmelted at 176 C. When purified by boiling in acetone, dissolution in hotdimethylformamide and precipitation with ethanol, the diester melted at197 199 c and was identified by elementary analysis. The free acidobtained as the monohydrate by hydrolysis as above in a yield of 89percent melted at 173 175 C, had a R; value of 0.55, and was identifiedby its equivalent weight and elementary analysis. It is practicallyinsoluble in water, acetone, ethyl acetate, the lower alkyl ethers,chloroform and low boiling petroleum fractions, but dissolves readily inwarm methanol, ethanol, isopropanol or glacial acetic acid. The sodiumand N- methylglucamine salts are so easily soluble in water thatsolutions containing more than 40 g/dl at 20 C may be prepared.

EXAMPLE 12 B-(4-N-Carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-amino-a-phenylpropionic (Compound L) A solution of27.1 g (0.035 mole) 4-N-carbethoxymethylcarbamyl-2,3 ,5,6-tetraiodobenzoyl chloride, 13.6 g (0.070 mole)a-phenyl-B-aminopropionic acid ethyl ester and 3.5 g (0.035 mole)freshly distilled triethylamine in 175 ml dimethylformamide was stirredat 100 C for 12 14 hours. The deeply red reaction solution was stirredinto a mixture of 850 ml water and 150 ml 2 N hydrochloric acid, wherebya reddish-buff crude diester was precipitated. It was filtered off,dried and recrystallized from 55 ml dimethylformamide and 150 ethanol.The yield was 21.7 g (66.5 percent), the melting point 297 300 C.

15.0 g Diester were dissolved in 79.5 concentrated sulfuric acid atslightly elevated temperature. The clear solution was poured over 15.8 gice, and the diluted liquid was added dropwise with vigorous stirring to950 Acid ml 2 N sodium hydroxide at 70 90 C. After minutes, the solutionwas clarified with active carbon and mixed with 100 m1 2 N hydrochloricacid to precipitate Compound 1.. which was filtered off and purified bydispersing it in several changes of hot water. When dried, it weighed 11.4 g (81 percent yield), had a melting point of 288 289 C (decomp.),and an R, value of 0.64. It was identified by its equivalent weight andelementary analysis:

eq. wt. 437; 26.1% C;

Calc. for C H LMO Found EXAMPLE l31-(4-N-methyl-N-carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-pyrrolidine- 2-carboxylic acid (Compound R) 245.4 g(0.347 Mole) tetraiodoterephthaloyl dichloride in 3,000 ml chloroformfree from alcohol were mixed with 43 g (0.367 mole) N- methylaminoaceticacid ethyl ester and 35.15 g (0.347 mole) triethylamine. The mixture wasstirred at boiling temperature for 7 hours, cooled to ambienttemperature, filtered, and washed with dilute hydrochloric acid andwater. It contained unreacted tetraiodoterephthaloyl dichloride,4-(N-methyl-N-carbethoxymethyl)-carbamyl-2,3,5,6-tetraiodobenzoylchloride (Compound a) and1,4-bis-(N-met'hyl-N-carbethoxymethyl)-carbamyl-2,3,5,6-tetraiodobenzene(Compound b).

The chloroform solution was extracted repeatedly with small amounts (2550 ml) concentrated sulfuric acid, whereby Compounds a and b weredissolved in the sulfuric acid phase and the acyl chloride group ofCompound a was hydrolyzed to the carboxyl group. The unchanged startingmaterial remained in the chloroform solution and was recovered from thesame in an amount of 45.3 g by evaporation to dryness and washing of theresidue with diethyl ether.

The combined sulfuric acid extracts were stirred into 1 kg ice, and theresulting precipitate was extracted with chloroform. The residueconsisted of 70 g 4-(N- methyl-N-carbethoxymethyl)-carbamyl-2,3,5,6-tetraiodobenzoic acid of MP. 228 229 C (decomp.) (Compound a). Thechloroform extract containing Compound b and more than half of Compounda was stirred with 400 ml water, and 1.0 N sodium hydroxide solution wasadded in small amounts so as not to raise the pH beyond 8 to 9. Compoundb remained unchanged, and Compound a entered the aqueous phase as thesodium salt. Saponification of the ester groups was avoided by keepingthe temperature low and controlling pH.

The weakly alkaline aqueous phase was washed with diethyl ether,filtered, purged of dissolved ether in a vacuum and acidified withhydrochloric acid. 4-N- Methyl-N-carbethoxymethylcarbamoyl-2,3,5,6-tetraiodobenzoic acid was thereby precipitated in an amount of 99 g,M.P. 227 228 C, for a total yield of 169 g (77.5 percent).

The 169 g 4-N-methyl-N-carbethoxymethylcarbamyl-2,3,5,6-tetraiodobenzoicacid recovered in two batches, as described above, were mixed with 750ml thionyl chloride, and the mixture was kept boiling for 1 2 hours withagitation. The excess of thionyl chloride was evaporated, and theresidue was repeatedly dissolved in chloroform free from alcohol andrecovered by evaporation to dryness. It was ultimately washed withpetroleum ether, and 179 g4-N-methyl-N-carbethoxymethylcarbamyl-Z,3,5,6-tetraiodobenzoyl chlorideof M.P. 160 161 C were obtained.

70.86 g (0.09 Mole) of the last-prepared acyl chloride, 19.78 g (0.135mole) L-proline ethyl ester, and 9.11 g (0.09 mole) triethylamine in 500ml 1,2- dichloroethane were kept at the boiling temperature withagitation for eight hours. The reaction mixture was extracted withhydrochloric acid and water, dried, and evaporated to dryness. Theresidue was dispersed in diethylether and recovered in purifiedcondition. It weighed 65.7 g (81.5 percent yield) and consisted of thediethyl ester of Compound R sintering at C, partly melting at 133 157 C,and decomposing at 180 205 C. A thin layer chromatogram on silica gelwith hexane/chloroform/glacial acetic acid 5:4:1 revealed the presenceof two isomers having R, values of 0.69 and 0.45 respectively. The moresoluble isomer was extracted with ml boiling isopropanol, and theresidue weighing 31.3 g melted at 2l7' 219 C and had an R; value of0.68. It was identified by microanalysis:

it dissolves only slightly in water, lower alcohols, ethers, acetone andethyl acetate, but is readily soluble in chloroform and warm glacialacetic acid.

30 g Diester (R; 0.68) were hydrolyzed in 150 ml ethanol by means of 84ml 1.0 N sodium hydroxide solution and 150 ml water, and thesaponification mixture was evaporated to dryness. The residual sodiumsalt was dissolved in water, and the solution was filtered and acidifiedto precipitate Compound R in an amount of 26.6 g (94.5 percent yield).1t sintered at 214 217 C, melted at 223 224C (decomp.), and had an R,value of 0.47. It was identified by elementary analysis:

Calculated for C nH l N2O5: Found:

5 EXAMPLE 14 B-[4-(2'-Carboxypyrrolidine)-carbonyl-2,3,5,6-tetraiodobenzoyl]-aminoa-ethylpropionic acid (Compound Q) In theprocedure of Example 13, N- methylaminoacetic acid ethyl ester wasreplaced with L-proline ethyl ester. 4-(2'-Carbethoxypyrrolidino)-carbonyl-2,3,5,6-tetraiodobenzoyl chloride of M.p. 96 99 C was obtainedas an intermediate from the corresponding benzoic acid derivative of MP.184 185 C 55.2 g (0.071 Mole) of the acyl chloride were refluxed in 300ml chloroform with 15.5 g (0.107 mole) B amino-a-ethylpropionic acidethyl esterand 7.2 g (0.071 mole) triethylamine for 18 hours. Thereaction mixture was extracted with hydrochloric acid and water, dried,and evaporated to dryness. Crude B-[4-(2'-carbethoxypyrrolidino)-carbonyl-2,3,5,6-tetraiodobenzoyl]-amino-a-ethylpropionic acid ethyl ester was recoveredin a yield of 65.3 g (100 percent). It was dissolved in 25 ml warmmethylisobutylketone, and the solution was cooled until crystallizationstarted. 150 M1 diethyl ether were then gradually added. The crystals ofthe pure diester were recovered, weighed 54.25 g (83 percent yield), andhad a melting point of 176 178 C. R, 0.6 (hexane/chloroformlglacialacetic acid 5:4:1). The diester was identified by microanalysis:

Calculated for C H LN O 28.66% C; 55.07% 1 Found 28.75% 55.12%

The free acid was obtained by saponifying 54 g diester in 300 ml boilingethanol with 140 ml 1 N sodium hydroxide solution and 300 ml water addedat a rate to keep the solution clear, and acidifying the solution of thesodium salt so obtained, as described in more detail in Example 13.Compound Q was recovered in an amount of 46.85 g (92.4 percent yield).M.P. 197

198 C. R,= 0.63. It was identified by elementary analysis and equivalentweight:

Calc. for C H LN O Found:

eq. wt. 433; 24.97% C; 58.62% 1 The acid is insoluble in water, veryslightly soluble in chloroform, ethers and benzene, but readily solublein methanol, ethanol, acetone, and glacial acetic acid.

EXAMPLE l5 acid whereby HCl gas was developed and a clear solution wasobtained. The solution was stirred into about 2 kg ice, and theresulting precipitate was filtered off with suction, and suspended in750 ml water. Enough sodium hydroxide solution was added to thesuspension until added phenolphthalein indicator showed a permanent pinkcolor. Undissolved material was removed by filtering, and the filtratewas acidified.

1 19 g 4-N-B-carbethoxybutylcarbamyl-2,3,5,6- tetraiodobenzoic acid wereprecipitated and recovered. The acid was converted to the acyl chlorideby refluxing with 700 g thionyl chloride. The crude benzoyl chloridederivative was obtained by evaporation of the excess thionyl chloride inan amount of 109 g. M.P. 238 240 C (decomp.). When recrystallized fromchlorobenzene, the compound melted at 240 (decomp.) and had an R, valueof 0.85 (hexane/chloroform/glacial acetic acid 514:1). It was identifiedby microanalysis:

Calc. for C H CILNQ Found 5 eq./mole halogen 4.93

EXAMPLE l6 ,8-(4-N-Methyl-N-carboxymethylcarbamyl-Z,3,5,6-tetraiodobenzoyl)-amino-a-ethylpropionic acid (Compound P) 47.24 g (0.06Mole) 4-N-methyl-N-carbethoxymethylcarbamyl-2,3,S,6-tetraiodobenzoylchloride, 14.52 g (0.1 mole) B-amino-a-ethylpropionic acid ethyl ester,and 6.01 g (0.06 mole) triethylamine were reacted in 250 ml dry, boilingchloroform free from alcohol for 30 to 40 hours with agitation. Thereaction mixture was extracted with hydrochloric acid and water, dried,and evaporated to dryness. The residue weighing 52.05 g (97 percentyield) was dissolved in 20 ml methylisobutylketone, and crystallizationwas induced by rubbing with a glass rod, whereupon 500 ml diethyl etherwere added.

The pure diester of Compound P was obtained in yield of 39.1 g (73percent) and had a melting point of 138 139 C and an R, value of 0.66(hexane/chloroform/glacial acetic acid 5:4: 1 It was identified byelementary analysis:

Calculated for C H LN O Found Calculated for C,.,H l N O,,: Found:

The free acid is insoluble in water, slightly soluble in ethers,low-boiling petroleum fractions, chloroform and benzene, but readilysoluble in lower alkanols, acetone and glacial acetic acid. The sodiumand N- methylglucamine salts form aqueous solutions of more than 50 g/dlat 20 C.

Two or more isomers were found to occur in asymmetrically substituteddiamides of tetraiodophthalic acid in instances not specificallydescribed in the preceding examples. They are thought to be due tosteric hindrance because of the space occupied by. the four iodine atomsattached to the benzene ring. The relatively low yields referred to insome examples are explained by the recovery of the prevailing isomeronly.

The compounds of the invention are applied orally or parenterally priorto cholecystography, and are combined with excipients practicallytransparent to X-rays in compositions in dosage form which may betablets, granules, capsules, solutions, suspensions or the like, as isconventional in galenic pharmacy. Solid excipients may be compoundedwith the free acids or with their salts with physiologically toleratedmetals and organic bases, and the alkali metal and alkanolamine saltsare preferred for the preparation of aqueous solutions though some ofthe acids form soluble non-toxic salts with metals outside the firstgroup of the Periodic Table of Elements and with many organic baseswhich are not alkanolamines, such as those commonly combined withtherapeutically effective anionic components. The following Examples 17to 23 are thus merely representative of presently preferred methods ofcombining the compounds of the invention with conventional excipients.

EXAMPLE 17 Compound I 399 g N-Methylglucamine 48.8 g Sodium hydroxide 30g 0.2 to make 100 ml Disodium edetate Bidistilled water The disodiumedetate was dissolved in a small portion of the water, and the otheringredients were added with stirring in the order in which they arelisted above. The solution was adjusted to pH 7.1 i 0.25, ultrafiltered,transferred to glass vials in batches of and ml, and sterilized. Itcontained approximately 250 mg iodine per milliliter.

The solutions were injected generally into the veins of the patient, butintramuscular injection has been used successfully in children whereveins of adequate size were not available. The necessary dosage wasdetermined individually in each case and amounted to 2 to 10 g iodineequivalent or about 4 to 20 g of Compound I. With dosage rates at thelower end of the range indicated, the injection was performed slowlyover a period of 5 to 16 minutes by means of a syringe. Drop infusionwas more practical with more than 5 or 6 g iodine equivalent, and tookan hour or longer.

Good cholecystograms were obtained about 30 to 180 minutes after theintravenous injection or 90 to 240 minutes after inception of theinfusion, and useful contrast was still found in many X-ray picturestaken 4,

8 and even 24 hours after application of the contrast agent.

The procedure outlined above is equally applicable to injectablesolutions of other contrast agents whose preparation is described in thefollowing Examples 18 and 19.

' EXAMPLE 18 A 'solution similar to that of Example 17 was preparedfrom:

Compound M 406 g N-Methylglucamine l46.8 g Sodium hydroxide l0 gDisodium edetate 0.3 Bidistilled water to make I00 ml The solution wasprepared as in the preceding example, transferred to vials having acapacity of 20 ml or to rubber-capped multiple-puncture vials of and 200ml capacity and sterilized. It contained about 255 mg iodine permilliliter.

EXAMPLE 19 Compound K (monohydrate) 422 g N-Methylglucamine 146.8 gSodium hydroxide l0 g Disodium edetate 0.3

Bidistilled water to make 100 ml An injectable solution was preparedaccording to the above formulation as described in Example 18 andsterilized in 20 ml vials for use in individual cholecystographi c testsand in l00 and 200 multiple-puncture vials. It contained about 255 mgiodine per ml.

EXAMPLE 20 5 kg Compound C were mixed in a kneading machine with 2liters of an aqueous starch dispersion containing 100 g corn starch. Alittle solid starch was added to make the moist-mixture less tacky. Itwas then granulated on a granulating machine, and the granules weredried in a vacuum. The finished granulate was mixed with 0.5 kg cornstarch and 25 g magnesium stearate, and the mixture was converted on atableting machine to tablets which contained 500 mg of Compound C.

Four to 12 tablets containing 1 to 3 grams iodine were given to patientson an empty stomach, and cholecystograms were made within 8 to 16 hoursafter ingestion. The upper limit of the range indicated (3 grams iodine)is usually preferred in adult patients. The same dosage rate applies tothe ingestible compositions described below in Examples 21 to 23.

EXAMPLE 21 The sodium salt of Compound H was prepared by mixingsolutions of stoichiometrically equivalent amounts of the free acid andof sodium hydroxide with the minimum amount of water necessary toproduce a clear solution. Two volumes ethanol were then added, andscraping of the vessel wall with a glass rod induced crystallization ofthe sodium salt. 5 Kilograms of the salt were intimately mixed with 0.75kg granulated sugar and 0.75 kg corn starch. The mixture was moistenedwith 1,000 ml 50 percent aqueous ethanol and granulated on aconventional granulating table.

The granules were dried, sieved, mixed with 0.65 kg corn starch, 0.05 kgtalcum and 0.05 kg magnesium stearate, and 10,000 tablets were preparedfrom the mixture, each tablet containing 500 mg of the active agent anda corresponding amount of the excipient transparent to X-rays.

The sodium salts, lithium salts and calcium salts of the other freeacids of the invention are prepared and compounded in an analogousmanner. If the addition of ethanol or isopropanol and scraping orseeding should not cause precipitation of a crystalline salt, theaqueous solvent mixture may have to be evaporated in a vacuum, and theresidue triturated with isopropanol to cause crystallization.

The water soluble salts of the several free acids of the invention withN-methylglucamine and other organic bases are prepared fromstoichiometrically equivalent amounts of acid and base mixed with justenough water or methanol to produce a solution from which the salt iseither precipitated by a large excess of ethanol or isopropanol asdescribed above or recovered by evaporation of the solvent. Thefollowing Examples 22-24 further illustrate the procedures for makingsalts of the invention.

EXAMPLE 22 A solution of 15.96 g Compound l (0.020 mole) and 7.81 g(0.040 mole) N-methylglucamine in 100 ml methanol was mixed with 250 mlisopropanol in a glass beaker. The inner wall of the container holdingthe amorphous suspension formed thereby was scraped with a glass rod,and the contents of the beaker were cooled to C, whereby a crystallineprecipitate was obtained. It was recovered by filtration with suction,washed with a little cold isopropanol and dried.

The practically pure salt was used in making solid X- ray contrast agentcompositions as described above. A small amount was saved for use inseeding later prepared batches.

EXAMPLE 23 A suspension of 16.88 g (0.02 mole) Compound K in 50 mlmethanol was mixed at boiling temperature with 80 ml 0.5 N methanolicsodium hydroxide. The clear solution so obtained was evaporated in avacuum until crystallization started, whereupon 300 ml isopropanol wereadded. The disodium salt of Compound K was precipitated in the form offine crystals which were recovered, dried and tableted as described inExample 21.

EXAMPLE 24 A hot saturated solution of 40.59 g Compound M (0.05 mole)and 19.52 g N-methylglucamine (0.10 mole) in methanol was stirred whilebeing cooled to 0 C and seeded with seed crystals previously prepared byevaporation of a portion of the solution. The crystallized salt wasfiltered off with suction, washed witha little methanol and dried. itwas then granulated and tableted as described above.

EXAMPLE 25 2 g Sodium salt of Compound I were prepared as described inExample 22 and dissolved in 50 g 0.05 percent aqueous sodium chloridesolution understerile condition. The solution so obtained was appliedrectally to a child prior to cholecystography, and X-ray images of goodcontrast were obtained.

The corresponding N-methylglucamine salts of Compound I and of otheracids of the invention may similarly be compounded for rectalapplication with sterile sodium chloride solution.

EXAMPLE 26 Granules prepared by the methods of Examples 20 and 21 werecoated with 25 percent (by weight) simple syrup in a dragee-makingkettle and were waxed thereafter, as is conventional. The dragees of thetwo batches contained about percent and 60 percent by weightrespectively of the two active agents.

EXAMPLE 27 750 g Compound G were stirred with 600 g sesame oil and gvegetal lecithin to make a paste which was distributed in 1,000 softgelatin capsules, each capsule containing about 459 mg combined iodine.

The manner of preparing injectable, ingestible, or rectally appliedcompositions of the invention from the compounds will be readilyapparent to those skilled in the art from Examples 17 to 27. The dosagerates will readily be selected to suit the patients weight and conditionfrom the indicated iodine contents.

What is claimed is:

1. A compound which is a member of the group consisting of a diamide oftetraiodoterephthalic acid of the formula an alkyl ester, and awater-soluble salt of said diamide with a nontoxic alkali metal, anon-toxic alkaline earth metal, or a non-toxic amine, in said formula Xbeing alkylene or phenyl-alkylene,

R being hydrogen, alkyl or phenyl-alkyl, or

X and R jointly being alkylene,

R being hydrogen or alkyl,

R being alkyl, carboxyalkyl, or carbalkoxy-alkyl, or

R and R jointly being alkylenoxy-alkylene, carboxy-alkylene, orcarbalkoxyalkylene, each alkyl and alkylene in said formula having notmore than five carbon atoms,

said HOOC-X-N-R being different from said 2. A diamide as set forth inclaim 1, wherein said R NR is N-carboxymethyl-N-methylamino, N-carboxyethylamino, N-carboxy-methyl-N-ethylamino or2-carboxypyrrolidyl-l 3. A diamide as set forth in claim 1, wherein X ismethylene, and R is methyl.

4. A diamide as set forth in claim 4, wherein said R NR, isN-2-carboxybutylamino or 2-carboxypyrrolidyl-l 5. A diamide as set forthin claim 1, wherein said HOOC-X-N-R is 2-carboxy-pyrrolidyl-l, and saidR ---NR is 2-carboxybutylamino.

6. A compound as set forth in claim 1, which is an alkanolamine salt ofsaid diamide.

7. A compound as set forth in claim 1, which is said diamide or a sodiumor N-methylglucamine salt of said diamide.

8. A compound as set forth in claim 1, wherein said diamide isB-(4-N-methyl-N-carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-amino-a-ethylpropionic acid.

9. A compound as set forth in claim 11, which is said diamide.

10. A compound as set forth in claim 1, wherein said

2. A diamide as set forth in claim 1, wherein said R2-N-R1 isN-carboxymethyl-N-methylamino, N-carboxyethylamino,N-carboxy-methyl-N-ethylamino or 2-carboxy-pyrrolidyl-1.
 3. A diamide asset forth in claim 1, wherein X is methylene, and R is methyl.
 4. Adiamide as set forth in claim 4, wherein said R2-N-R1 isN-2-carboxybutylamino or 2-carboxy-pyrrolidyl-1.
 5. A diamide as setforth in claim 1, wherein said HOOC-X-N-R is 2-carboxy-pyrrolidyl-1, andsaid R2-N-R1 is 2-carboxybutylamino.
 6. A compound as set forth in claim1, which is an alkanolamine salt of said diamide.
 7. A compound as setforth in claim 1, which is said diamide or a sodium or N-methylglucaminesalt of said diamide.
 8. A compound as set forth in claim 1, whereinsaid diamide is Beta-(4-N-methyl-N-carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-amino-Alpha -ethylpropionic acid.
 9. A compound as set forth in claim 11,which is said diamide.
 10. A compound as set forth in claim 1, whereinsaid diamide is Beta-(4-N-carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-amino- Alpha-ethylpropionic acid.
 11. A compound as set forth in claim 1, whereinsaid diamide is1-(4-N-methyl-N-carboxymethylcarbamyl-2,3,5,6-tetraiodobenzoyl)-pyrrolidine-2-carboxylic acid.
 12. A compound as set forth in claim 1, wherein saiddiamide is1-(4-N-methylcarbamyl-2,3,5,6-tetraiodobenzoyl)-pyrrolidine-2-carboxylicacid.